Organ-specific autoimmune diseases in man are common and cause significant morbidity and mortality. These diseases, including type 1 diabetes (IDDM), are chronic and, especially in diabetes, late complications are common. Such diseases are therefore very costly to the individual and, given their estimated prevalence of more than 10% (lifetime prevalence of IDDM ) 0.3%-1.0%). Are very costly to society as well. In contrast to the complexity of human and NOD mouse IDDM, where the large number of genetic factors with relatively small effects has complicated the isolation and characterization of these factors, our data suggest that four major genetic factors control IDDM in our crosses in the BB rat model for IDDM. (1ddm1-4). The disease process is also influenced by physiological/environmental factors since in the BB rat the animals are lymphopenic from birth but early insulitis is not detected until about 45 days of age. Our long-term objective is therefore to explain the molecular mechanisms of how these four genetic factors interact to spontaneously induce organ-specific autoimmunity, insulitis and diabetes as well as thyroiditis. We expect that segments of the disease pathway defined by these factors will also be involved in the pathogenesis of other organ-specific autoimmune diseases, and thus help to define organ- specific and organ-independent disease processes. The Specific Aims of Project 1 are: 1. Complete the positional cloning of Iddm1/Lyp, and analyze its expression and autoreactivity it produces. 2. Determine candidate Lyp gene (Ajm pa) function by studying its expression and by constructing a mouse knock-out allele. 3. Map the Iddm3 and Iddm4 genes, clone by position and determine their interactions with Lyp and the major histocompatibility complex (Iddm2). Project 1 interacts with Projects 2 and 3 for sequencing the Lyp/Iddm1 region and clone Lyp by position; with Project 3 for genotyping, virtual mapping of the Lyp/Iddm1 region and for the production of speed congenic rats as well as for the mapping and positional cloning for Iddm3 and Iddm4. As the positional cloning of Iddm1/Lyp is in the final stage of gene identification, that subproject has moved to Project 1 in order to take advantage of Project 1 as the main source of IDDM disease expertise in the study of the immunological effects of the Lyp gene once it is conclusively identified. Project 1 has made considerable progress during the current funding period. All rats for Projects 1-3 are generated in Seattle. The Speed Congenic technology has been critical to our objective to clone and sequence the genetic factors that control spontaneous diabetes in the BB rat. Project 1 is central to the interaction with Project 2 and 3 and provides all the different rats needed to complete the mission of this program project, as well as all immunological and IDDM-specific analysis.